Triazolopyridinone PDE10 inhibitors

ABSTRACT

The present invention is directed to triazolopyridinone compounds which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington&#39;s disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US2012/064281 filed on Nov. 9, 2012, which claims the benefit under35 U.S.C. 119(e) of U.S. Provisional Application No. 61/559,375, filedNov. 14, 2011.

FIELD OF THE INVENTION

The invention relates generally to compounds which act as inhibitors ofthe phosphodiesterase (PDE) 10 enzyme, compositions and therapeutic usesthereof.

BACKGROUND OF THE INVENTION

Schizophrenia is a debilitating disorder affecting the psychic and motorfunctions of the brain. It is typically diagnosed in individuals intheir early to mid-twenties and symptoms include hallucinations anddelusions or at the other extreme, anhedonia or social withdrawal.Across the spectrum, the symptoms are indicative of cognitive impairmentand functional disabilities. Notwithstanding improvements inantipsychotic treatments, current therapies, including typical(haloperidol) and atypical (clozapine or olanzapine) antipsychotics,have been less than acceptable and result in an extremely high rate ofnoncompliance or discontinuation of medication. Dissatisfaction withtherapy is attributed to lack of efficacy or intolerable andunacceptable side affects. The side effects have been associated withsignificant metabolic, extrapyramidal, prolactic and cardiac adverseevents. See Lieberman et al., N. Engl. J. Med. (2005) 353:1209-1223.

While multiple pathways are believed to be involved with thepathogenesis of schizophrenia leading to psychosis and cognitiondeficits, much attention has focused on the role of glutamate/NMDAdysfunction associated with cyclic guanosine monophosphate (cGMP) levelsand the dopaminergic D2 receptor associated with cyclic adenosinemonophosphate (cAMP). These ubiquitous second messengers are responsiblefor altering the function of many intracellular proteins. Cyclic AMP isthought to regulate the activity of cAMP-dependent protein kinase (PKA),which in turns phosphorylates and regulates many types of proteinsincluding ion channels, enzymes and transcription factors. Similarly,cGMP is also responsible for downstream regulation of kinases and ionchannels.

One pathway for affecting the levels of cyclic nucleotides, such as cAMPand cGMP, is to alter or regulate the enzymes that degrade theseenzymes, known as 3′,5′-cyclic nucleotide specific phosphodiesterases(PDEs). The PDE superfamily includes twenty one genes that encode foreleven families of PDEs. These families are further subdivided based oncatalytic domain homology and substrate specificity and include the 1)cAMP specific, PDE4A-D, 7A and 7B, and 8A and 8B, 2) cGMP specific, PDE5A, 6A-C, and 9A, and 3) those that are dual substrate, PDE 1A-C, 2A, 3Aand 3B, 10A, and 11A. The homology between the families, ranging from20% to 45% suggests that it may be possible to develop selectiveinhibitors for each of these subtypes.

The identification of PDE10 was reported by three groups independentlyand was distinguished from other PDEs on the basis of its amino acidsequence, functional properties, and tissue distribution (Fujishige etal., J. Biol. Chem. (1999) 274:18438-18445; Loughney et al., Gene (1999)234: 109-117; Soderling et al., PNAS, USA (1999) 96: 7071-7076). ThePDE10 subtype at present consists of a sole member, PDE10A, havingalternative splice variants at both the N-terminus (three variants) andC-terminus (two variants), but that does not affect the GAF domain inthe N-terminus or the catalytic site in C-terminus. The N-terminussplice variants, PDE10A1 and PDE10A2, differ in that the A2 variant hasa PKA phosphorylation site that upon activation, i.e. PKAphosphorylation in response to elevated cAMP levels, results inintracellular changes to the localization of the enzyme. PDE10A isunique relative to other PDE families also having the conserved GAFdomain in that its ligand is cAMP, while for the other GAF-domain PDEsthe ligand is cGMP (Kehler et al., Expert Opin. Ther. Patents (2007)17(2): 147-158). PDE10A has limited but high expression in the brain andtestes. The high expression in the brain and, in particular, the neuronsof the striatum, unique to PDE10, suggests that inhibitors thereto maybe well suited from treating neurological and psychiatric disorders andconditions.

Inhibition of PDE 10 is believed to be useful in the treatment ofschizophrenia and a wide variety of conditions or disorders that wouldbenefit from increasing levels of cAMP and/or cGMP within neurons,including a variety neurological, psychotic, anxiety and/or movementdisorders. Accordingly, agents that inhibit PDE10 and especially PDE10Awould be desirable as therapeutics for neurological and psychiatricdisorders.

SUMMARY OF THE INVENTION

The present invention is directed to triazolopyridinone compounds whichare useful as therapeutic agents for the treatment of central nervoussystem disorders associated with phosphodiesterase 10 (PDE10). Thepresent invention also relates to the use of such compounds for treatingneurological and psychiatric disorders, such as schizophrenia, psychosisor Huntington's disease, and those associated with striatal hypofunctionor basal ganglia dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:A is heterocyclyl;R^(1a), R^(1b) and R^(1c) may be absent if the valency of A does notpermit such substitution and are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one or more        substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heteroaryl, where the heteraryl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently        selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R¹⁴,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R¹⁴,        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R¹⁴,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R¹⁴,        -   (f) phenyl, which is unsubstituted or substituted with R¹⁴,            and        -   (g) heteroaryl, which is unsubstituted or substituted with            R¹⁴,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R^(2a), R^(2b) and R^(2c) are independently selected from the        group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocyclyl, where the heterocyclyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R³, R⁴, R⁵ and R⁶ are independently selected from the group        consisting of:    -   (1) hydrogen,    -   (2) halogen, and    -   (3) —C₁₋₆alkyl,    -   or R³ and R⁵ are joined together to form a cyclopropyl ring;        R¹³ is selected from the group consisting of:    -   (1) halogen,    -   (2) hydroxyl,    -   (3) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (4) —O_(n)—(C₁₋₃)perfluoroalkyl,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R¹⁴,    -   (9) —(C═O)_(m)—O_(n)-heteroaryl, where the heteroaryl is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R¹⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆alkyl,    -   (6) —O(C═O)—C₁₋₆alkyl,    -   (7) —NH—C₁₋₆alkyl,    -   (8) phenyl,    -   (9) heteroaryl,    -   (10) —CO₂H, and    -   (11) —CN;        p is 0 or 1, wherein when p is 0 a bond is present;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein A, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), and R^(2c) aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein A, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), and R^(2c) aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc:

wherein A, R^(1a), R^(1b), R^(1c) and R^(2a) are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaId:

wherein A, R^(1a), R^(1b), R^(1c) and R^(2a) are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIe:

wherein A, R^(1a), R^(1b), R^(1c) and R^(2c) are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIf:

wherein A, R^(1a), R^(1b), R^(1c) and R^(2c) are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein A isselected from the group consisting of:

-   -   (1) benzimidazolyl,    -   (2) imidazopyridinyl,    -   (3) naphthyridinyl,    -   (4) pyridopyrimidinone,    -   (5) quinazolinone,    -   (6) quinolinyl,    -   (7) quinoxalinyl, and    -   (8) tetrahydroquinolinyl.

An embodiment of the present invention includes compounds wherein A isselected from the group consisting of:

-   -   (1) benzimidazol-2-yl,    -   (2) imidazo[1,2-a]pyridin-2-yl,    -   (3) 1,5-naphthyridin-2-yl,    -   (4) pyrido[2,3-d]pyrimidin-4(3H)-one,    -   (5) quinazolin-4(3H)-one,    -   (6) quinoxalin-2-yl,    -   (7) quinolin-2-yl, and    -   (8) 5,6,7,8-tetrahydroquinolin-2-yl.

An embodiment of the present invention includes compounds wherein A isquinazolin-4(3H)-one. An embodiment of the present invention includescompounds wherein A is quinolin-2-yl. An embodiment of the presentinvention includes compounds wherein A is 1,5-naphthyridin-2-yl. Anembodiment of the present invention includes compounds wherein A is5,6,7,8-tetrahydroquinolin-2-yl. An embodiment of the present inventionincludes compounds wherein A is benzimidazol-2-yl. An embodiment of thepresent invention includes compounds wherein A is thiazol-4-yl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        C₃₋₆cycloalkyl, halogen, hydroxyl, phenyl or naphthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        C₁₋₆alkyl, halogen, hydroxyl, or phenyl,

(7) heteroaryl, wherein heteroaryl is selected from pyrrolyl,imidazolyl, indolyl, pyridyl, pyrazolyl, and pyrimidinyl, which isunsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, and

-   -   (8) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds wherein R^(1b)is hydrogen, R^(1c) is hydrogen and R^(1a) is independently selectedfrom the group consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) bromo,    -   (5) methyl,    -   (6) methoxy,    -   (7) (methyl)cyclopropyl-,    -   (8) cyclopropyl,    -   (9) (methoxy)phenyl-, and    -   (10) (methyl)phenyl-.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or naphthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heterocyclyl, wherein heterocyclyl is selected from        imidazolyl, isothiazolyl, oxazolyl, morpholinyl, pyrazolyl,        pyridyl, tetrazolyl, pyrazinyl, and thiazolyl, which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂, and    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds wherein R^(2b)is hydrogen, and R^(2a) and R^(2c) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) bromo,    -   (5) methyl,    -   (6) isopropoxy,    -   (7) methoxy,    -   (8) t-butoxy,    -   (9) imidazolyl,    -   (10) isothiazolyl,    -   (11) oxazolyl,    -   (12) morpholinyl,    -   (13) pyrazolyl,    -   (14) pyridyl,    -   (15) tetrazolyl, and    -   (16) thiazolyl.

An embodiment of the present invention includes compounds wherein R^(2b)is hydrogen, R^(2c) is hydrogen and R^(2a) is selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) bromo,    -   (5) methyl,    -   (6) isopropoxy,    -   (7) methoxy,    -   (8) t-butoxy,    -   (9) imidazolyl,    -   (10) isothiazolyl,    -   (11) oxazolyl,    -   (12) morpholinyl,    -   (13) pyrazolyl,    -   (14) pyridyl,    -   (15) tetrazolyl, and    -   (16) thiazolyl.

An embodiment of the present invention includes compounds wherein R^(2b)is hydrogen, R^(2c) is hydrogen and R^(2a) is selected from the groupconsisting of:

-   -   (1) chloro,    -   (2) methyl,    -   (3) isopropoxy,    -   (4) oxazolyl,    -   (5) pyrazolyl,    -   (6) pyridyl, and    -   (7) thiazolyl.

An embodiment of the present invention includes compounds wherein R^(2b)is hydrogen, R^(2a) is hydrogen and R^(2c) is selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) bromo,    -   (5) methyl,    -   (6) isopropoxy,    -   (7) methoxy,    -   (8) t-butoxy,    -   (9) imidazolyl,    -   (10) isothiazolyl,    -   (11) oxazolyl,    -   (12) morpholinyl,    -   (13) pyrazolyl,    -   (14) pyridyl,    -   (15) tetrazolyl, and    -   (16) thiazolyl.    -   An embodiment of the present invention includes compounds        wherein R^(2b) is hydrogen, R^(2a) is hydrogen and R^(2c) is        selected from the group consisting of:    -   (1) chloro,    -   (2) methyl,    -   (3) isopropoxy,    -   (4) oxazolyl,    -   (5) pyrazolyl,    -   (6) pyridyl, and    -   (7) thiazolyl.

An embodiment of the present invention includes compounds wherein p is0.

An embodiment of the present invention includes compounds wherein p is 1and R³ and R⁵ are joined together to form a cyclopropyl ring.

An embodiment of the present invention includes compounds wherein R³ ishydrogen, R⁴ is hydrogen, R⁵ is hydrogen, and R⁶ is hydrogen.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluorine, chlorine, bromine and iodine.Similarly, “alkyl”, as well as other groups having the prefix “alk”,such as alkoxy, alkanoyl, means carbon chains which may be linear orbranched or combinations thereof. C₁₋₆, as in C₁₋₆alkyl is defined toidentify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear orbranched arrangement, such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.“Alkylene” means a straight or branched chain of carbon atoms with agroup substituted at both ends, such as —CH₂CH₂— and —CH₂CH₂CH₂—.“Alkenyl” means a carbon chain which contains at least one carbon-carbondouble bond, and which may be linear or branched or combinations thereofsuch that C₂₋₆alkenyl is defined to identify the group as having 2, 3,4, 5 or 6 carbons which incorporates at least one double bond, which maybe in a E- or a Z-arrangement, including vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like. “Alkynyl” means a carbon chain which contains at least onecarbon-carbon triple bond, and which may be linear or branched orcombinations thereof, such as ethynyl, propargyl, 3-methyl-1-pentynyl,2-heptynyl and the like. “Cycloalkyl” means a mono-, bi- or tri-cyclicstructure, optionally combined with linear or branched structures,having the indicated number of carbon atoms, such as cyclopropyl,cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl,2-ethyl-1-bicyclo[4.4.0]decyl, and the like. “Alkoxy” means an alkoxygroup of a straight or branched chain having the indicated number ofcarbon atoms. C₁₋₆alkoxy, for example, includes methoxy, ethoxy,propoxy, isopropoxy, and the like. The term “heterocyclyl” as usedherein includes both unsaturated heterocyclic moieties comprising amono- or bicyclic aromatic rings with at least one ring containing aheteroatom selected from N, O and S, and each ring containing 5 or 6atoms (i.e. “heteroaryl”) and saturated heterocyclic moieties comprisingmono- or bicyclic saturated rings with at least one ring containing aheteroatom selected from N, O and S, and each ring containing 3, 5 or 6atoms. Examples of “heteroaryl” include benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl,furo(2,3-b)pyridyl, imidazolyl, indolinyl, indolyl, dihydroindolyl,indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl,isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl,oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydroquinoxalinyl,tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and N-oxides thereof. Examples of saturated heterocyclicmoieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl,tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxidesthereof.

A group which is designated as being substituted with substituents maybe substituted with multiple numbers of such substituents. A group whichis designated as being independently substituted with substituents maybe independently substituted with multiple numbers of such substituents.

The compounds of the present invention may contain one or morestereogenic centers and can thus occur as racemates, racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. Any formulas, structures or names ofcompounds described in this specification that do not specify aparticular stereochemistry are meant to encompass any and all existingisomers as described above and mixtures thereof in any proportion. Whenstereochemistry is specified, the invention is meant to encompass thatparticular isomer in pure form or as part of a mixture with otherisomers in any proportion.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

The present invention also includes all pharmaceutically acceptableisotopic variations of a compound of the Formula I in which one or moreatoms is replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen such as ²Hand ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N,oxygen such as ¹⁵O, ¹⁷O and ¹⁸P, phosphorus such as ³²P, sulfur such as³⁵S, fluorine such as ¹⁸F, iodine such as ²³I and ¹²⁵I, and chlorinesuch as ³⁶Cl. Certain isotopically-labelled compounds of Formula I, forexample those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with heavier isotopes such as deuterium, i.e.²H, may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labelled compoundsof Formula I can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples using appropriate isotopically-labelledreagents in place of the non-labelled reagent previously employed.

It will be understood that, as used herein, references to the compoundsof present invention are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds or inother synthetic manipulations. The compounds of the present inventionmay be administered in the form of a pharmaceutically acceptable salt.The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, cupric,cuprous, ferric, ferrous, lithium, magnesium, manganic, manganous,potassium, sodium, zinc and the like salts. Particular embodimentsinclude the ammonium, calcium, magnesium, potassium, and sodium salts.Salts in the solid form may exist in more than one crystal structure,and may also be in the form of hydrates. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylamino-ethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. When the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particular embodiments citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of the present invention are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention are the specific compounds disclosed in theExamples and herein. The subject compounds are useful in a method oftreating a neurological or psychiatric disorder associated with PDE10dysfunction in a patient such as a mammal in need of such inhibitioncomprising the administration of an effective amount of the compound. Inaddition to primates, especially humans, a variety of other mammals canbe treated according to the method of the present invention. The subjectcompounds are useful in a method of inhibiting PDE10 activity in apatient such as a mammal in need of such inhibition comprising theadministration of an effective amount of the compound. The subjectcompounds are also useful for treating a neurological or psychiatricdisorder associated with striatal hypofunction or basal gangliadysfunction in a mammalian patient in need thereof. In addition toprimates, especially humans, a variety of other mammals can be treatedaccording to the method of the present invention.

The present invention is directed to a compound of the present inventionor a pharmaceutically acceptable salt thereof for use in medicine. Thepresent invention is further directed to a use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for treating a neurological or psychiatricdisorder associated with PDE10 dysfunction in a mammalian patient inneed thereof. The present invention is further directed to a use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for treating a neurologicalor psychiatric disorder associated with striatal hypofunction or basalganglia dysfunction in a mammalian patient in need thereof.

“Treating” or “treatment of” a disease state includes: 1) preventing thedisease state, i.e. causing the clinical symptoms of the disease statenot to develop in a subject that may be exposed to or predisposed to thedisease state, but does not yet experience or display symptoms of thedisease state; 2) inhibiting the disease state, i.e., arresting thedevelopment of the disease state or its clinical symptoms; 3) orrelieving the disease state, i.e., causing temporary or permanentregression of the disease state or its clinical symptoms.

The subject treated in the present methods is generally a mammal, inparticular, a human being, male or female, in whom therapy is desired.The term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response ofa tissue, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician. It isrecognized that one skilled in the art may affect the neurological andpsychiatric disorders by treating a patient presently afflicted with thedisorders or by prophylactically treating a patient afflicted with suchdisorders with an effective amount of the compound of the presentinvention. As used herein, the terms “treatment” and “treating” refer toall processes wherein there may be a slowing, interrupting, arresting,controlling, or stopping of the progression of the neurological andpsychiatric disorders described herein, but does not necessarilyindicate a total elimination of all disorder symptoms, as well as theprophylactic therapy to retard the progression or reduce the risk of thenoted conditions, particularly in a patient who is predisposed to suchdisease or disorder.

Applicants propose that inhibitors of PDE10 and, in particularinhibitors of PDE10A, will provide therapeutic benefit to thoseindividuals suffering from psychiatric and cognitive disorders. Theunique and exclusive distribution of PDE10A in the medium spinyprojection neurons of the striatum, which form the principle site forcortical and dopaminergic input within basal ganglia, suggests that itmay be possible and desirable to identify inhibitors of PDE10 toameliorate or eliminate unwanted cellular signaling within this site.Without wishing to be bound by any theory, Applicants believe thatinhibition of PDE10A in the striatum will result in increased cAMP/cGMPsignaling and striatal output, which has the potential to restorebehavioral inhibition that is impaired in cognitive disease such asschizophrenia. Regulation and integration of glutamatergic anddopaminergic inputs will enhance cognitive behavior, while suppressingor reducing unwanted behavior. Thus, in one embodiment, compounds of theinvention provide a method for treating or ameliorating diseases orconditions in which striatal hypofunction is a prominent feature or onesin which basal ganglia dysfunction plays a role, such as, Parkinson'sdisease, Huntington's disease, schizophrenia, obsessive-compulsivedisorders, addiction and psychosis. Other conditions for which theinhibitors described herein may have a desirable and useful effectinclude those requiring a reduction in activity and reduced response topsychomotor stimulants or where it would be desirable to reduceconditional avoidance responses, which is often predictive of clinicalantipsychotic activity.

As used herein, the term “'selective PDE10 inhibitor” refers to anorganic molecule that effectively inhibits an enzyme from the PDE10family to a greater extent than enzymes from the PDE 1-9 or PDE11families. In one embodiment, a selective PDE10 inhibitor is an organicmolecule having a Ki for inhibition of PDE10 that is less than or aboutone-tenth that for a substance that is an inhibitor for another PDEenzyme. In other words, the organic molecule inhibits PDE 10 activity tothe same degree at a concentration of about one-tenth or less than theconcentration required for any other PDE enzyme. Preferably, a selectivePDE10 inhibitor is an organic molecule, having a Ki for inhibition ofPDE10 that is less than or about one-hundredth that for a substance thatis an inhibitor for another PDE enzyme. In other words, the organicmolecule inhibits PDE10 activity to the same degree at a concentrationof about one-hundredth or less than the concentration required for anyother PDE enzyme. A “selective PDE10 inhibitor” can be identified, forexample, by comparing the ability of an organic molecule to inhibitPDE10 activity to its ability to inhibit PDE enzymes from the other PDEfamilies. For example, an organic molecule may be assayed for itsability to inhibit PDE10 activity, as well as PDE1A, PDE1B, PDE1C,PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B,PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, and/or PDE11A.

Phosphodiesterase enzymes including PDE10 have been implicated in a widerange of biological functions. This has suggested a potential role forthese enzymes in a variety of disease processes in humans or otherspecies. The compounds of the present invention have utility in treatinga variety of neurological and psychiatric disorders.

In a specific embodiment, compounds of the present invention provide amethod for treating schizophrenia or psychosis comprising administeringto a patient in need thereof an effective amount of a compound of thepresent invention. The Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorders. As used herein, the term“schizophrenia or psychosis” includes the diagnosis and classificationof these mental disorders as described in DSM-IV-TR and the term isintended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, conditions or diseases such as schizophrenia or psychosis, includingschizophrenia (paranoid, disorganized, catatonic, undifferentiated, orresidual type), schizophreniform disorder, schizoaffective disorder, forexample of the delusional type or the depressive type, delusionaldisorder, psychotic disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition andsubstance-induced or drug-induced (for example psychosis induced byalcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants,opioids, phencyclidine, ketamine and other dissociative anaesthetics,and other psychostimulants), psychosispsychotic disorder, psychosisassociated with affective disorders, brief reactive psychosis,schizoaffective psychosis, “schizophrenia-spectrum” disorders such asschizoid or schizotypal personality disorders, personality disorder ofthe paranoid type, personality disorder of the schizoid type, illnessassociated with psychosis (such as major depression, manic depressive(bipolar) disorder, Alzheimer's disease and post-traumatic stresssyndrome), including both the positive and the negative symptoms ofschizophrenia and other psychoses.

In another specific embodiment, the compounds of the present inventionprovide a method for treating cognitive disorders comprisingadministering to a patient in need thereof an effective amount of acompound of the present invention. The DSM-IV-TR also provides adiagnostic tool that includes cognitive disorders including dementia,delirium, amnestic disorders and age-related cognitive decline. As usedherein, the term “cognitive disorders” includes the diagnosis andclassification of these disorders as described in DSM-IV-TR and the termis intended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, disorders that comprise as a symptom a deficiency in attentionand/or cognition, such as dementia (associated with Alzheimer's disease,ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebraltrauma, vascular problems or stroke, alcoholic dementia or otherdrug-related dementia, AIDS, HIV disease, Parkinson's disease,Huntington's disease, Pick's disease, Creutzfeldt Jacob disease,perinatal hypoxia, other general medical conditions or substance abuse),Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, andFronto temperal dementia, delirium, amnestic disorders or age relatedcognitive decline.

In another specific embodiment, compounds of the present inventionprovide a method for treating anxiety disorders comprising administeringto a patient in need thereof an effective amount of a compound of thepresent invention. The DSM-IV-TR also provides a diagnostic tool thatincludes anxiety disorders as generalized anxiety disorder,obsessive-compulsive disorder and panic attack. As used herein, the term“anxiety disorders” includes the diagnosis and classification of thesemental disorders as described in DSM-IV-TR and the term is intended toinclude similar disorders described in other sources. Disorders andconditions encompassed herein include, but are not limited to, anxietydisorders such as, acute stress disorder, agoraphobia, generalizedanxiety disorder, obsessive-compulsive disorder, panic attack, panicdisorder, post-traumatic stress disorder, separation anxiety disorder,social phobia, specific phobia, substance-induced anxiety disorder andanxiety due to a general medical condition.

In another specific embodiment, compounds of the present inventionprovide a method for treating substance-related disorders and addictivebehaviors comprising administering to a patient in need thereof aneffective amount of a compound of the present invention. The DSM-IV-TRalso provides a diagnostic tool that includes persisting dementia,persisting amnestic disorder, psychotic disorder or anxiety disorderinduced by substance abuse, and tolerance of, dependence on orwithdrawal from substances of abuse. As used herein, the term“substance-related disorders and addictive behaviors” includes thediagnosis and classification of these mental disorders as described inDSM-IV-TR and the term is intended to include similar disordersdescribed in other sources. Disorders and conditions encompassed hereininclude, but are not limited to, substance-related disorders andaddictive behaviors, such as substance-induced delirium, persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder, drug addiction, tolerance, and dependence or withdrawal fromsubstances including alcohol, amphetamines, cannabis, cocaine,hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives,hypnotics or anxiolytics.

In another specific embodiment, compounds of the present inventionprovide a method for treating obesity or eating disorders associatedwith excessive food intake, and complications associated therewith,comprising administering to a patient in need thereof an effectiveamount of a compound of the present invention. At present, obesity isincluded in the tenth edition of the International Classification ofDiseases and Related Health Problems (ICD-10) (1992 World HealthOrganization) as a general medical condition. The DSM-IV-TR alsoprovides a diagnostic tool that includes obesity in the presence ofpsychological factors affecting medical condition. As used herein, theterm “obesity or eating disorders associated with excessive food intake”includes the diagnosis and classification of these medical conditionsand disorders described in ICD-10 and DSM-IV-TR and the term is intendedto include similar disorders described in other sources. Disorders andconditions encompassed herein include, but are not limited to, obesity,bulimia nervosa and compulsive eating disorders.

In another specific embodiment, compounds of the present inventionprovide a method for treating mood and depressive disorders comprisingadministering to a patient in need thereof an effective amount of acompound of the present invention. As used herein, the term “mood anddepressive disorders” includes the diagnosis and classification of thesemedical conditions and disorders described in the DSM-IV-TR and the termis intended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, bipolar disorders, mood disorders including depressive disorders,major depressive episode of the mild, moderate or severe type, a manicor mixed mood episode, a hypomanic mood episode, a depressive episodewith atypical features, a depressive episode with melancholic features,a depressive episode with catatonic features, a mood episode withpostpartum onset, post-stroke depression; major depressive disorder,dysthymic disorder, minor depressive disorder, premenstrual dysphoricdisorder, post-psychotic depressive disorder of schizophrenia, a majordepressive disorder superimposed on a psychotic disorder such asdelusional disorder or schizophrenia, a bipolar disorder, for example,bipolar I disorder, bipolar II disorder, cyclothymic disorder,depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders.

In another specific embodiment, compounds of the present inventionprovide a method for treating pain comprising administering to a patientin need thereof an effective amount of a compound of the presentinvention. Particular pain embodiments are bone and joint pain(osteoarthritis), repetitive motion pain, dental pain, cancer pain,myofascial pain (muscular injury, fibromyalgia), perioperative pain(general surgery, gynecological), chronic pain and neuropathic pain.

In other specific embodiments, compounds of the invention providemethods for treating other types of cognitive, learning and mentalrelated disorders including, but not limited to, learning disorders,such as a reading disorder, a mathematics disorder, or a disorder ofwritten expression, attention-deficit/hyperactivity disorder,age-related cognitive decline, pervasive developmental disorderincluding autistic disorder, attention disorders such asattention-deficit hyperactivity disorder (ADHD) and conduct disorder; anNMDA receptor-related disorder, such as autism, depression, benignforgetfulness, childhood learning disorders and closed head injury; aneurodegenerative disorder or condition, such as neurodegenerationassociated with cerebral trauma, stroke, cerebral infarct, epilepticseizure, neurotoxin poisoning, or hypoglycemia-inducedneurodegeneration; multi-system atrophy; movement disorders, such asakinesias and akinetic-rigid syndromes (including, Parkinson's disease,drug-induced parkinsonism, post-encephalitic parkinsonism, progressivesupranuclear palsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification),medication-induced parkinsonism (such as, neuroleptic-inducedparkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremor), Huntington'sdisease, dyskinesia associated with dopamine agonist therapy, Gilles dela Tourette's syndrome, epilepsy, muscular spasms and disordersassociated with muscular spasticity or weakness including tremors;dyskinesias, including tremor (such as, rest tremor, postural tremor,intention tremor and essential tremor), restless leg syndrome, chorea(such as Sydenham's chorea, Huntington's disease, benign hereditarychorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea andhemiballism), myoclonus (including, generalised myoclonus and focalmyoclonus), tics (including, simple tics, complex tics and symptomatictics), dystonia (including, generalised, iodiopathic, drug-induced,symptomatic, paroxymal, and focal (such as blepharospasm, oromandibular,spasmodic, spasmodic torticollis, axial dystonia, hemiplegic anddystonic writer's cramp)); urinary incontinence; neuronal damage(including ocular damage, retinopathy or macular degeneration of theeye, tinnitus, hearing impairment and loss, and brain edema); emesis;and sleep disorders, including insomnia and narcolepsy. Of the disordersabove, the treatment of schizophrenia, bipolar disorder, depression,including unipolar depression, seasonal depression and post-partumdepression, premenstrual syndrome (PMS) and premenstrual dysphoricdisorder (PDD), learning disorders, pervasive developmental disorders,including autistic disorder, attention disorders includingAttention-Deficit/Hyperactivity Disorder, autism, tic disordersincluding Tourette's disorder, anxiety disorders including phobia andpost traumatic stress disorder, cognitive disorders associated withdementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease,spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment andloss are of particular importance.

The activity of the compounds in accordance with the present inventionas PDE10 inhibitors may be readily determined without undueexperimentation using a fluorescence polarization (FP) methodology thatis well known in the art (Huang, W., et al., J. Biomol Screen, 2002, 7:215). In particular, the compounds of the following examples hadactivity in reference assays by exhibiting the ability to inhibit thehydrolysis of the phosphosphate ester bond of a cyclic nucleotide. Anycompound exhibiting a Ki (inhibitory constant) below 1 μM would beconsidered a PDE10 inhibitor as defined herein.

In a typical experiment the PDE10 inhibitory activity of the compoundsof the present invention was determined in accordance with the followingexperimental method. PDE10A2 was amplified from human fetal brain cDNA(Clontech, Mountain View, Calif.) using a forward primer correspondingto nucleotides 56-77 of human PDE10A2 (Accession No. AF127480, GenbankIdentifier 4894716), containing a Kozak consensus sequence, and areverse primer corresponding to nucleotides 2406-2413 of human PDE10A2(Accession No. AF127480, Genbank Identifier 4894716). Amplification withEasy-A polymerase (Stratagene, La Jolla, Calif.) was 95° C. for 2minutes followed by thirty three cycles of 95° C. for 40 seconds, 55° C.for 30 seconds, and 72° C. for 2 minutes 48 seconds. Final extension was72° C. for 7 minutes. The PCR product was TA cloned into pcDNA3.2-TOPO(Invitrogen, Carlsbad, Calif.) according to standard protocol. AD293cells with 70-80% confluency were transiently transfected with humanPDE10A2/pcDNA3.2-TOPO using Lipofectamine 2000 according to manufacturerspecifications (Invitrogen, Carlsbad, Calif.). Cells were harvested 48hours post-transfection and lysed by sonication (setting 3, 10×5 secpulses) in a buffer containing 20 mM HEPES, 1 mM EDTA and proteaseinhibitor cocktail (Roche). Lysate was collected by centrifugation at75,000×g for 20 minutes. Supernatant containing the cytoplasmic fractionwas used for evaluation of PDE10A2 activity. The fluorescencepolarization assay for cyclic nucleotide phosphodiesterases wasperformed using an IMAP® FP kit supplied by Molecular Devices,Sunnyvale, Calif. (product #R8139). IMAP® technology has been appliedpreviously to phosphodiesterase assays (Huang, W., et al., J. BiomolScreen, 2002, 7: 215). Assays were performed at room temperature in384-well microtiter plates with an incubation volume of 20.2 μl.Solutions of test compounds were prepared in DMSO and serially dilutedwith DMSO to yield 8 μL of each of 10 solutions differing by 3-fold inconcentration, at 32 serial dilutions per plate. 100% inhibition isdetermined using a known PDE10 inhibitor, which can be any compound thatis present at 5,000 times its Ki value in the assay described asfollows, such as papaverine (see Siuciak, et al. Neuropharmacology(2006) 51:386-396; Becker, et al. Behav Brain Res (2008) 186(2):155-60;Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):785-795),2-{4-[pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]phenoxymethyl}quinolinesuccinic acid or2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]quinolinesuccinic acid (see Schmidt, et al. J Pharmacol Exp Ther (2008)325:681-690; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):785-795). 0% of inhibition is determined by using DMSO (1% finalconcentrations).

A Labcyte Echo 555 (Labcyte, Sunnyvale, Calif.) is used to dispense 200nL from each well of the titration plate to the 384 well assay plate. Asolution of enzyme (1/1600 dilution from aliquots; sufficient to produce20% substrate conversion) and a separate solution of FAM-labeled cAMPPDE from Molecular Devices (product #R7506), at a final concentration of50 nM are made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl₂,0.05% NaN₃ 0.01% Tween-20, and 1 mM DTT). The enzyme and the substrateare then added to the assay plates in two consecutive additions of 10μL, and then shaken to mix. The reaction is allowed to proceed at roomtemperature for 30 minutes. A binding solution is then made from the kitcomponents, comprised of 80% Solution A, 20% Solution B and bindingreagent at a volume of 1/600 the total binding solution. The enzymaticreaction is stopped by addition of 60 μL of the binding solution to eachwell of the assay plates and the plates are sealed and shaken for 10seconds. The plate was incubated at room temperature for at least onehour prior to determining the fluorescence polarization (FP). Theparallel and perpendicular fluorescence of each well of the plate wasmeasured using a Perkin Elmer Enyision™ plate reader (Waltham, Mass.).

Fluorescence polarization (mP) was calculated from the parallel (5) andperpendicular (P) fluorescence of each sample well and the analogousvalues for the median control well, containing only substrate (So andPo), using the following equation:Polarization(mP)=1000*(S/So−P/Po)/(S/So+P/Po).

Dose-inhibition profiles for each compound were characterized by fittingthe mP data to a four-parameter equation given below. The apparentinhibition constant (K_(I)), the maximum inhibition at the low plateaurelative to “100% Inhibition Control” (Imax; e.g. 1=>same as thiscontrol), the minimum inhibition at the high plateau relative to the “0%Inhibition Control” (Imin, e.g. 0=>same as the no drug control) and theHill slope (nH) are determined by a non-linear least squares fitting ofthe mP values as a function of dose of the compound using an in-housesoftware based on the procedures described by Mosser et al., JALA, 2003,8: 54-63, using the following equation:

${mP} = {\frac{\left( {{0\%\mspace{14mu}{mP}} - {100\%\mspace{14mu}{mP}}} \right)\left( {{I\;\max} - {I\;\min}} \right)}{1 + \left\lbrack \frac{\lbrack{Drug}\rbrack}{\left( {10^{- {pK}_{1}}\left( {1 + \frac{\lbrack{Substrate}\rbrack}{K_{M}}} \right)} \right.} \right\rbrack^{nH}} + {100\%\mspace{14mu}{mP}} + {\left( {{0\%\mspace{14mu}{mP}} - {100\%\mspace{14mu}{mP}}} \right)\left( {1 - {I\;\max}} \right)}}$

The median signal of the “0% inhibition controls” (0% mP) and the mediansignal of the “100% inhibition controls” (100% mP) are constantsdetermined from the controls located in columns 1-2 and 23-24 of eachassay plate. An apparent (K_(m)) for FAM-labeled cAMP of 150 nM wasdetermined in separate experiments through simultaneous variation ofsubstrate and selected drug concentrations.

Selectivity for PDE10, as compared to other PDE families, was assessedusing the IMAP® technology. Rhesus PDE2A3 and Human PDE10A2 enzyme wasprepared from cytosolic fractions of transiently transfected HEK cells.All other PDE's were GST Tag human enzyme expressed in insect cells andwere obtained from BPS Bioscience (San Diego, Calif.): PDE1A (Cat#60010), PDE3A (Cat #60030), PDE4A1A (Cat #60040), PDE5A1 (Cat #60050),PDE6C (Cat #60060), PDE7A (Cat #60070), PDE8A1 (Cat #60080), PDE9A2 (Cat#60090), PDE11A4 (Cat #60110).

Assays for PDE 1 through 11 were performed in parallel at roomtemperature in 384-well microtiter plates with an incubation volume of20.2 μL. Solutions of test compounds were prepared in DMSO and seriallydiluted with DMSO to yield 30 μL of each of ten solutions differing by3-fold in concentration, at 32 serial dilutions per plate. 100%inhibition was determined by adding buffer in place of the enzyme and 0%inhibition is determined by using DMSO (1% final concentrations). ALabcyte POD 810 (Labcyte, Sunnyvale, Calif.) was used to dispense 200 nLfrom each well of the titration plate to make eleven copies of the assayplate for each titration, one copy for each PDE enzyme. A solution ofeach enzyme (dilution from aliquots, sufficient to produce 20% substrateconversion) and a separate solution of FAM-labeled cAMP or FAM-labeledcGMP from Molecular Devices (Sunnyvale, Calif., product #R7506 or cGMP#R7508), at a final concentration of 50 nM were made in the assay buffer(10 mM Tris HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃ 0.01% Tween-20, and 1mM DTT). Note that the substrate for PDE2 is 50 nM FAM cAMP containing1000 nM of cGMP. The enzyme and the substrate were then added to theassay plates in two consecutive additions of 10 μL and then shaken tomix. The reaction was allowed to proceed at room temperature for 60minutes. A binding solution was then made from the kit components,comprised of 80% Solution A, 20% Solution B and binding reagent at avolume of 1/600 the total binding solution. The enzymatic reaction wasstopped by addition of 60 μL of the binding solution to each well of theassay plate. The plates were sealed and shaken for 10 seconds. Theplates were incubated at room temperature for one hour, then theparallel and perpendicular fluorescence was measured using a TecanGenios Pro plate reader (Tecan, Switzerland). The apparent inhibitionconstants for the compounds against all 11 PDE's was determined from theparallel and perpendicular fluorescent readings as described for PDE10FP assay using the following apparent K_(M) values for each enzyme andsubstrate combination: PDE1A (FAM cGMP) 70 nM, rhesus PD2A3 (FAM cAMP)10,000 nM, PDE3A (FAM cAMP) 50 nM, PDE4A1A (FAM cAMP) 1500 nM, PDE5A1(FAM cGMP) 400 nM, PDE6C (FAM cGMP) 700 nM, PDE7A (FAM cAMP) 150 nM,PDE8A1 (FAM cAMP) 50 nM, PDE9A2 (FAM cGMP) 60 nM, PDE10A2 (FAM cAMP) 150nM, PDE11A4 (FAM cAMP) 1000 nM. The intrinsic PDE10 inhibitory activityof a compound which may be used in accordance with the present inventionmay be determined by these assays.

The compounds of the following examples had activity in inhibiting thehuman PDE 10 enzyme in the aforementioned assays, generally with an Kiof less than about 1 μM. Many of compounds within the present inventionhad activity in inhibiting the human PDE 10 enzyme in the aforementionedassays, generally with an Ki of less than about 0.1 μM. Additional datais provided in the following Examples. Such a result is indicative ofthe intrinsic activity of the compounds in use as inhibitors of thePDE10 enzyme. In general, one of ordinary skill in the art wouldappreciate that a substance is considered to effectively inhibit PDE10activity if it has a Ki of less than or about 1 μM, preferably less thanor about 0.1 μM. The present invention also includes compounds withinthe generic scope of the invention which possess activity as inhibitorsof other phosphodiesterase enzymes.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein. The subject compounds are furtheruseful in a method for the prevention, treatment, control, amelioration,or reduction of risk of the aforementioned diseases, disorders andconditions in combination with other agents. The compounds of thepresent invention may be used in combination with one or more otherdrugs in the treatment, prevention, control, amelioration, or reductionof risk of diseases or conditions for which compounds of the presentinvention or the other drugs may have utility, where the combination ofthe drugs together are safer or more effective than either drug alone.Such other drug(s) may be administered, by a route and in an amountcommonly used therefor, contemporaneously or sequentially with acompound of the present invention. When a compound of the presentinvention is used contemporaneously with one or more other drugs, apharmaceutical composition in unit dosage form containing such otherdrugs and the compound of the present invention may be desirable.However, the combination therapy may also includes therapies in whichthe compound of the present invention and one or more other drugs areadministered on different overlapping schedules. It is also contemplatedthat when used in combination with one or more other active ingredients,the compounds of the present invention and the other active ingredientsmay be used in lower doses than when each is used singly. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acompound of the present invention. The above combinations includecombinations of a compound of the present invention not only with oneother active compound, but also with two or more other active compounds.Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention. Theweight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, such as about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Accordingly, the subject compounds may be used alone or in combinationwith other agents which are known to be beneficial in the subjectindications or other drugs that affect receptors or enzymes that eitherincrease the efficacy, safety, convenience, or reduce unwanted sideeffects or toxicity of the compounds of the present invention. Thesubject compound and the other agent may be co-administered, either inconcomitant therapy or in a fixed combination.

In one embodiment, the subject compound may be employed in combinationwith anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen,vitamin E, and anti-amyloid antibodies.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine,aripiprazole, atypical antipsychotics, bentazepam, benzoctamine,brotizolam, bupropion, busprione, butabarbital, butalbital, capuride,carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam,cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine,clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol,fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam,glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium,lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin,mephobarbital, meprobamate, methaqualone, midaflur, midazolam,nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam,paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine,phenelzine, phenobarbital, prazepam, promethazine, propofol,protriptyline, quazepam, quetiapine, reclazepam, risperidone,roletamide, secobarbital, sertraline, suproclone, temazepam,thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,ziprasidone, zolazepam, zolpidem, and salts thereof, and combinationsthereof, and the like, or the subject compound may be administered inconjunction with the use of physical methods such as with light therapyor electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexyl)hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.Lisuride and pramipexol are commonly used in a non-salt form.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with thesubject compound maybe in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound may beemployed in combination with acetophenazine, alentemol, aripiprazole,amisulpride, benzhexyl, bromocriptine, biperiden, chlorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid,phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine;duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone andviloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate,diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans. The terms “administration of” and or“administering a” compound should be understood to mean providing acompound of the invention or a prodrug of a compound of the invention tothe individual in need of treatment.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. Such term in relation to pharmaceutical composition,is intended to encompass a product comprising the active ingredient(s),and the inert ingredient(s) that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients. Ingeneral, pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition the active object compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by mixing acompound of the present invention and a pharmaceutically acceptablecarrier.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients that are suitable for themanufacture of tablets. The tablets may be uncoated or they may becoated by known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredients are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions, oily suspensions,dispersible powders or granules, oil-in-water emulsions, and sterileinjectable aqueous or oleagenous suspension may be prepared by standardmethods known in the art. By “pharmaceutically acceptable” it is meantthe carrier, diluent or excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein. The dosage of active ingredientin the compositions of this invention may be varied, however, it isnecessary that the amount of the active ingredient be such that asuitable dosage form is obtained. The active ingredient may beadministered to patients (animals and human) in need of such treatmentin dosages that will provide optimal pharmaceutical efficacy. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans. The dosage range will generally be about 0.5mg to 1.0 g. per patient per day which may be administered in single ormultiple doses. In one embodiment, the dosage range will be about 0.5 mgto 500 mg per patient per day; in another embodiment about 0.5 mg to 200mg per patient per day; and in yet another embodiment about 5 mg to 50mg per patient per day. Pharmaceutical compositions of the presentinvention may be provided in a solid dosage formulation such ascomprising about 0.5 mg to 500 mg active ingredient, or comprising about1 mg to 250 mg active ingredient. The pharmaceutical composition may beprovided in a solid dosage formulation comprising about 1 mg, 5 mg, 10mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsand the requisite intermediates are in some cases commerciallyavailable, or can be prepared according to literature procedures or asillustrated herein. The compounds of this invention may be prepared byemploying reactions as shown in the following schemes, in addition toother standard manipulations that are known in the literature orexemplified in the experimental procedures. Substituent numbering asshown in the schemes does not necessarily correlate to that used in theclaims and often, for clarity, a single substituent is shown attached tothe compound where multiple substituents are allowed under thedefinitions hereinabove. Reactions used to generate the compounds ofthis invention are prepared by employing reactions as shown in theschemes and examples herein, in addition to other standard manipulationssuch as ester hydrolysis, cleavage of protecting groups, etc., as may beknown in the literature or exemplified in the experimental procedures.Starting materials are made according to procedures known in the art oras illustrated herein. The following abbreviations are used herein: Me:methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl;Ac: acetyl; THF: tetrahydrofuran; Boc: tert-butyloxycarbonyl; DIPEA:N,N-diisopropylethylamine; DPPA: diphenylphosphorylazide; EDC:N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; EtOAc: ethyl acetate;HOBt: hydroxybenzotriazole hydrate; TEA: triethylamine; DMF:N,N-dimethylformamide; rt: room temperature; HPLC: high performanceliquid chromatography; NMR: nuclear magnetic resonance; TLC: thin-layerchromatography. The compounds of the present invention can be preparedin a variety of fashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

As depicted in Scheme A, a 2-halopyridine (A-1) is reacted withhydrazine to produce aryl hydrazine A-2. The aryl hydrazine is treatedwith carbonyldiimidazole (CDI) to give the triazolopyridinone core A-3.The triazolopyridinone is then made to undergo conjugate addition to avinyl-substituted heterocycle under basic conditions, yielding subjectcompounds A-4. A reactive handle on the triazolopyridinone, such asbromine, is further modified by, for example, a cross-coupling reaction,to provide subject compounds A-5.

As shown in Scheme B, 4-phenylimidazole (B-1) is treated withiodomethane under basic conditions to afford B-2. On deprotonation withn-butyllithium, B-2 reacts with oxirane to produce alcohol B-3, whichcan be elaborated to subject compounds B-4 under Mitsunobu reactionconditions in the presence of triazolopyridinone A-3. A reactive handleon the triazolopyridinone, such as bromine, is further modified by, forexample, a nucleophilic aromatic substitution reaction, to providesubject compounds B-5.

As illustrated in Scheme C, alcohol C-1 undergoes Mitsunobu reactionwith A-3 to provide triazolopyridinones C-2. A reactive handle on thetriazolopyridinone, such as bromine, is further modified by, forexample, a cross-coupling reaction, to provide subject compounds C-3.

Example 1

2-vinylquinoline (1-2)

2-chloroquinoline (1-1) (1.00 g, 6.1 mmol) in toluene (25 mL) wassparged with N₂ gas for 5 min, and tributyl(vinyl)stannane (2.52 g, 2.33mL, 8.0 mmol) and tetrakis(triphenylphosphine)palladium (0.353 g, 0.31mmol) were added. The mixture was heated at 125° C. for 1 h, then cooledand concentrated in vacuo. The residue was suspended in CH₂Cl₂ (20 mL)and purified by silica gel flash column chromatography (80 g cartridge),eluting with 0-30% EtOAc/hexanes over 20 min. The fractions containingthe desired product (1-2) were pooled, and after solvent removal invacuo, 700 mg (74%) of a clear oil were obtained. LC/MS: m/z(M+H)=156.0.

3-bromo-2-hydrazinylpyridine (1-4)

To 3-bromo-2-chloropyridine (1-3) (12.5 g, 65 mmol) in THF (100 mL) wasadded hydrazine (10.4 g, 10.2 mL, 325 mmol). The mixture was heated toreflux and stirred vigorously for 16 h. An additional portion ofhydrazine (5.1 g, 5.0 mL, 159 mmol) was added and the reaction washeated for another 24 h. After cooling, the mixture was concentrated invacuo, suspended in water (50 mL), and extracted with EtOAc (1×350 mL,1×50 mL). Combined organic layers were washed with brine (50 mL), driedover MgSO₄, filtered, and concentrated in vacuo. The resulting crudeproduct (1-4) was used in the subsequent step without furtherpurification. LC/MS: m/z (M+H)=187.9.

8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1-5)

To a solution of 1-4 (5.0 g, 26.6 mmol) in THF (50 mL) was addedcarbonyldiimidazole (5.61 g, 34.6 mmol), and the heterogeneous mixturewas stirred for 2 h. The reaction was diluted with water (150 mL) andEtOAc (150 mL), causing a precipitate to form. The mixture was filteredthrough a sintered glass filter, yielding 2.0 g (35%) of 1-5 as a tansolid. ¹H NMR (300 MHz, DMSO-d₆) δ12.73 (s, 1H), 7.88 (dd, J=7.2, 0.9Hz, 1H), 7.58 (dd, J=7.2, 0.9 Hz, 1H), 6.51 (app t, J=7.2 Hz, 1H).

8-bromo-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pridin-3(2H)-one(1-6)

2-Vinylquinoline (1-2) (218 mg, 1.40 mmol) and triazolopyridinone 1-5(250 mg, 1.17 mmol) were placed in a microwave vial and dissolved in NMP(3 mL). To the mixture was added catalytic powdered KOH (13 mg, 0.234mmol), and the vial was capped and heated at 160° C. under microwaveirradiation for 20 min. After cooling, the mixture was diluted withCH₂Cl₂ (100 mL) and washed with water (25 mL) and brine (25 mL). Theorganic layer was dried over MgSO₄, filtered, and concentrated in vacuo.The crude material was purified by silica gel flash columnchromatography (40 g cartridge), eluting with 20-100% EtOAc/hexanes. Thefractions containing the desired product (1-6) were pooled, and aftersolvent removal in vacuo, 240 mg (52%) of a fluffy yellow solid wereobtained. ¹H NMR (300 MHz, CHCl₃-d) δ 8.07 (d, J=8.4 Hz, 1H), 8.02 (d,J=8.5 Hz, 1H), 7.77 (app t, J=8.0 Hz, 2H), 7.68 (t, J=7.7 Hz, 1H), 7.50(t, J=7.5 Hz, 1H), 7.38-7.30 (m, 2H), 6.39 (dd, J=7.2, 6.7 Hz, 1H), 4.61(t, J=7.6 Hz, 2H), 3.57 (t, J=7.6 Hz, 2H); HRMS (ES) 369.0345 (M+H)found, 369.0349 required.

Example 2

2-bromo-6-hydrazinylpyridine (2-2)

To a solution of 2-bromo-6-fluoropyridine (2-1) (1.0 g, 5.68 mmol) inTHF (10 mL) was added hydrazine (0.91 g, 0.89 mL, 28.4 mmol). Afterstirring for 1 h room temperature, the mixture was heated at 65° C. for1 h. The mixture was cooled, diluted with EtOAc (200 mL), washed withwater (10 mL) and brine (10 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. The resulting crude product (2-2) was used in thesubsequent step without further purification. ¹H NMR (300 MHz, CHCl₃-d):δ 7.32 (app t, J=7.8 Hz, 1H), 6.82 (dd, J=7.8, 0.6 Hz, 1H), 6.67 (dd,J=7.8, 0.6 Hz, 1H), 5.93 (s, 1H), 3.80 (s, 2H).

5-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (2-3)

To a solution of 2-2 (1.1 g, 5.85 mmol) in THF (50 mL) was addedcarbonyldiimidazole (1.14 g, 7.02 mmol), and the mixture was stirred for1 h. The reaction was diluted with water (150 mL) and EtOAc (150 mL),causing a precipitate to form. The mixture was filtered through asintered glass filter, yielding 0.8 g (64%) of 2-3 as a tan solid. ¹HNMR (300 MHz, CHCl₃-d) δ 9.34 (s, 1H), 7.03 (m, 1H), 6.85 (m, 1H), 6.59(m, 1H).

5-bromo-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(2-4)

2-Vinylquinoline (1-2) (218 mg, 1.40 mmol) and triazolopyridinone 2-3(250 mg, 1.17 mmol) were placed in a microwave vial and dissolved in NMP(2 mL). To the mixture was added catalytic powdered KOH (10 mg, 0.18mmol), and the vial was capped and heated at 130° C. under microwaveirradiation for 20 min. After cooling, the mixture was diluted withCH₂Cl₂ (100 mL) and washed with water (25 mL) and brine (25 mL). Theorganic layer was dried over MgSO₄, filtered, and concentrated in vacuo.The crude material was purified by silica gel flash columnchromatography (40 g cartridge), eluting with 25-100% EtOAc/hexanes. Thefractions containing the desired product (2-4) were pooled, and aftersolvent removal in vacuo, 40 mg (9%) of a white solid were obtained. ¹HNMR (400 MHz, CHCl₃-d): δ 8.08 (d, J=8.4 Hz, 1H), 8.03 (d, J=8.4 Hz,1H), 7.78 (d, J=8.0 Hz, 1H), 7.69 (m, 1H), 7.50 (app t, J=7.6 Hz, 1H)7.32 (d, J=8.8 Hz, 1H), 7.00 (d, J=11.6 Hz, 1H), 6.81 (dd, J=9.6, 7.2Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 4.51 (t, J=7.2 Hz, 2H), 3.52 (t, J=7.2Hz, 2H). HRMS (ES) 369.0346 (M+H) found, 369.0349 required.

Example 3

5-bromo-2-hydrazinylpyridine (3-2)

To 5-bromo-2-fluoropyridine (3-1) (46 g, 261 mmol) in THF (460 mL) wasadded hydrazine (41.9 g, 41.0 mL, 1.31 mol). The mixture was heated toreflux and stirred vigorously for 2 h. After cooling, the reactionmixture was diluted with water (200 mL) and extracted with EtOAc (3×500mL). The combined organic layers were washed with brine, dried overMgSO4, filtered, and concentrated in vacuo. The resulting crude product(3-2) was used in the subsequent step without further purification.LC/MS: m/z (M+H)=187.9.

6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3-3)

To a solution of 3-2 (2.0 g, 10.6 mmol) in dichloroethane (106 mL) wasadded triphosgene (3.16 g, 10.64 mmol). The reaction mixture was stirredat room temperature for 3 days. An off-white precipitate formed, whichwas washed with dichloroethane (100 mL) and dried in vacuo to give 2.03g (89%) of 3-3 as a tan solid. LC/MS: m/z (M+H)=213.9.

6-bromo-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]-triazolo[4,3-a]pyridin-3(2H)-one(3-4)

In a 1-dram vial were placed 2-(quinolin-2-yl)ethanol (405 mg, 2.80mmol), DIAD (472 mg, 2.34 mmol) and triphenylphosphine (613 mg, 2.34mmol) in THF (11.7 mL). The mixture was stirred at room temperature for10 min, and 3-3 (600 mg, 2.80 mmol) was added in one portion. Thereaction was further stirred for 10 min. The crude product was driedunder stream of N₂ and purified by reversed phase HPLC to give 480 mg(55%) of 3-4. HRMS (ES) 369.0348 (M+H) found, 369.0349 required.

Example 4

8-(oxazol-2-yl)-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(4-1)

A solution of bromide 1-6 (43 mg, 0.116 mmol) in THF (2 mL) in amicrowave vial was sparged with N₂ gas for 5 min, and2-(tributylstannyl)oxazole (83 mg, 0.233 mmol) andtetrakis(triphenylphosphine)palladium (13 mg, 0.012 mmol) were added.The vial was capped and heated at 125° C. under microwave irradiationfor 20 min, then another 30 min at 130° C. An additional portion of2-(tributylstannyl)oxazole (50 mg, 0.140 mmol) was added, and the vialwas heated at 85° C. in an oil bath for 16 h. After cooling, thereaction mixture was directly purified by silica gel flash columnchromatography (12 g cartridge), eluting with 40-100% EtOAc/hexanes then2% EtOH/EtOAc. The fractions containing the desired product (4-1) werepooled, and after solvent removal in vacuo, 6.8 mg (16%) of a yellowsolid were obtained. ¹H NMR (300 MHz, CHCl₃-d): δ 8.07 (d, J=8.4 Hz,1H), 8.02 (d, J=7.8 Hz, 1H), 7.92 (dd, J=6.9, 1.2 Hz, 1H), 7.88 (dd,6.9, 1.2 Hz, 1H), 7.80 (d, J=0.6 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.68(ddd, J=8.4, 7.2, 1.5 Hz, 1H), 7.50 (ddd, Jr=7.8, 6.6, 1.2 Hz, 1H), 7.35(s, 1H), 7.33 (s, 1H), 6.64 (t, J=7.2 Hz, 1H), 4.69 (t, J=7.5 Hz, 2H),3.61 (t, J=7.5 Hz, 2H). HRMS (ES) 358.1299 (M+H) found, 358.1302required.

Example 5

5-(pyridin-4-yl)-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(5-1)

Triazolopyridinone 2-4 (40 mg, 0.11 mmol) and pyridin-4-ylboronic acid(27 mg, 0.22 mmol) were placed in a microwave vial and dissolved indioxane (1 mL). To the mixture was added 1 M aq. Cs₂CO₃ solution (0.22mL, 0.22 mmol). The mixture was then sparged with N₂ gas for 3 min, andbis(tri-tert-butylphosphine)palladium (5.5 mg, 0.011 mmol) was added.The vial was capped and heated at 100° C. under microwave irradiationfor 30 min. After cooling, the reaction mixture was diluted with EtOAc(100 mL), washed with water (30 mL) and brine (30 mL), dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel flash column chromatography (12 g cartridge), eluting with 0-10%MeOH/CH₂Cl₂. The fractions containing the desired product (5-1) werepooled, and after solvent removal in vacuo, 8.0 mg (20%) of a yellowsolid were obtained. ¹H NMR (400 MHz, CHCl₃-d): δ 8.63 (dd, J=4.9, 1.5Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.68 (ddd, J=8.4, 6.8, 1.6 Hz, 1H), 7.53-7.48 (m, 1H), 7.31 (d,J=8.4 Hz, 1H), 7.26 (d, J=6.0 Hz, 2H), 7.16 (d, J=9.6 Hz, 1H), 7.08 (dd,J=9.6, 6.4 Hz, 1H), 6.36 (d, J=6.4 Hz, 1H), 4.49 (t, J=7.2 Hz, 2H), 3.51(t, J=7.2 Hz, 2H). HRMS (ES) 368.1508 (M+H) found, 368.1509 required.

Example 6

5-morpholino-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(6-1)

In a 5 mL microwave vial was placed 2-4 (221 mg, 0.599 mmol) andmorpholine (2.0 g, 2.0 mL, 23 mmol). The mixture was heated at 120° C.under microwave irradiation for 20 min. After cooling, the reactionmixture was purified by reversed phase HPLC to give 191 mg (85%) of 6-1.¹H NMR (500 MHz, DMSO-d₆): δ 8.51 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.2 Hz,1H), 7.96 (d, J=8.5 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.69-7.60 (m, 2H),7.00 (t, J=8.1 Hz, 1H), 6.67 (d, J=9.3 Hz, 1H), 5.72 (d, J=7.0 Hz, 1H),4.32 (t, J=7.0 Hz, 2H), 3.63 (m, 4H), 3.10 (s, 1H), 2.99 (s, 1H), 2.93(s, 4H). HRMS (ES) 376.1765 (M+H) found, 376.1771 required.

Example 7

5-acetyl-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(7-1)

In a 20 mL microwave vial were placed 2-4 (327 mg, 0.886 mmol),tributyl(1-methoxyvinyl)stannane (0.640 g, 1.771 mmol), andbis(tri-tert-butylphosphine)palladium (45 mg, 0.089 mmol) in THF (8.8mL). The vial was sealed and the reaction was heated at 140° C. undermicrowave irradiation for 15 min. The reaction mixture was directlypurified by silica gel flash column chromatography (100 g cartridge),eluting with 0-90% 1:1 EtOAc/(20:1:1 EtOH/NH₄OH/H₂O)/hexanes. Thefractions containing the desired product (7-1) were pooled, and aftersolvent removal in vacuo, 310 mg of enol ether were obtained. Thisintermediate was placed in 20 mL scintillation vial, suspended inanhydrous diethyl ether, treated with 1 N HCl in diethyl ether, andstirred for 1 h at room temperature. The suspension was filtered toobtain 7-1 as a bright yellow solid, which was used in the subsequentstep without further purification. LC/MS: m/z (M+H)=333.1.

5-(2-hydroxy-1-(4-methoxyphenyl)propan-2-yl)-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(7-2)

In a flame-dried, 5 mL microwave vial was placed 7-1 (20 mg, 0.054 mmol)in THF (0.54 mL) under dry N₂ gas. The reaction mixture was cooled to−78° C., and a 0.5 M solution of (4-methoxyphenyl)magnesium bromide inTHF (0.119 mmol, 0.24 mL) was added. After stirring for 15 min, thereaction was quenched with sat. aq. NH₄Cl (0.25 mL) and diluted withCH₂Cl₂ (2 mL). The mixture was transferred to a phase separator column,and the organic layer was collected and dried under a stream of N₂ gas.The crude product was purified by reversed phase HPLC (eluting with20-60% acetonitrile/water with 0.1% NH₄OH modifier). Pure fractions werepooled and dried to give 6.3 mg (26%) of 7-2. HRMS (ES) 441.1911 found(M+H) found, 441.1923 required.

Example 8

3-oxo-2-(2-(quinolin-2-yl)ethyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylicacid (8-1)

In a flame-dried, 5 mL microwave vial was placed 2-4 (199 mg, 0.54 mmol)in anhydrous THF (2.5 mL) under dry N₂ gas. The reaction mixture wascooled to −78° C. and a 1.6 M solution of n-butyllithium in hexanes(0.371 mL, 0.59 mmol) was added dropwise. After stirring for 10 min at−78° C., dry CO₂ gas was bubbled through the solution for 2 min. Thereaction was quenched with sat. aq. NH₄Cl, allowed to warm to roomtemperature, and then extracted with EtOAc (2×10 mL). The combinedorganic layers were concentrated in vacuo. The crude product wastriturated with hexanes and CH₂Cl₂, then filtered to give 97 mg (54%) of8-1 as a pink solid. The material was used in the subsequent stepwithout further purification. LC/MS: m/z (M+H)=335.1.

3-oxo-N-(pyridin-3-yl)-2-(2-(quinolin-2-yl)ethyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxamide(8-2)

In a 1-dram vial was placed 8-1 (15 mg, 0.045 mmol) in anhydrous DMF(0.45 mL). To this solution was added EDC (8.0 mg, 0.045 mmol), HOAT(6.0 mg, 0.045 mmol), diisopropylethylamine (0.008 mL, 0.045 mmol), and3-aminopyridine (0.001 g, 0.049 mmol). The reaction mixture was heatedat 40° C. and stirred for 16 h. The crude reaction mixture was thendirectly purified by reversed phase HPLC to give 15.0 mg (80%) of 8-2.¹H NMR (500 MHz, DMSO-d₆): δ 11.06 (s, 1H), 8.84 (s, 1H), 8.44 (d, J=8.8Hz, 1H), 8.40 (d, J=5.0 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.0Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.79 (t, J=7.4 Hz, 1H), 7.64-7.55 (m,2H), 7.53 (t, J=6.5 Hz, 1H), 7.32 (d, J=9.3 Hz, 1H), 7.24 (t, J=7.9 Hz,1H), 6.85 (d, J=6.5 Hz, 1H), 4.39 (t, J=7.6 Hz, 2H), 3.46 (t, J=7.6 Hz,2H). HRMS (ES) 411.1546 (M+H) found, 411.1567 required.

Example 9

6-pyridin-3-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(9-1)

In a 2 mL microwave vial were placed 3-4 (15 mg, 0.041 mmol),3-(tributylstannyl)pyridine (16 mg, 0.045 mmol), andbis(tri-tert-butylphosphine)palladium (2 mg, 0.004 mmol) in anhydrousDMF (0.4 mL). The vial was sealed and the reaction was heated at 135° C.under microwave irradiation for 15 min. The reaction mixture wasfiltered, and the filtrate was directly purified by reversed phase HPLCto give 5.0 mg (35%) of 9-1. ¹H NMR (500 MHz, DMSO-d₆): δ 9.03 (s, 1H),8.67 (d, J=5.0 Hz, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H),8.29 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.83 (t,J=7.6 Hz, 1H), 7.69-7.61 (m, 4H), 7.38 (d, J=9.8 Hz, 1H), 4.47 (t, J=6.9Hz, 2H), 2.54 (t, J=6.9 Hz, 2H). HRMS (ES) 368.1502 (M+H) found,368.1509 required.

Example 10

2-vinyl-1,5-naphthyridine (10-2)

2-chloro-1,5-naphthyridine (10-1) (35 g, 213 mmol) in toluene (420 mL)was treated with tributyl(vinyl)stannane (101 g, 93.4 mL, 319 mmol) andtetrakis(triphenylphosphine)palladium (36.9 g, 31.9 mmol). The mixturewas heated at 140° C. under microwave irradiation for 20 min, thencooled and concentrated in vacuo. The residue was purified by silica gelflash column chromatography, eluting with 0-100% EtOAc/heptane. Thefractions containing the desired product (10-2) were pooled, and aftersolvent removal in vacuo, 19 g (57%) of the product were obtained.LC/MS: m/z (M+H)=157.2.

2-(2-(1,5-naphthyridin-2-yl)ethyl)-8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(10-3)

2-Vinyl-1,5-naphthyridine (10-2) (109 mg, 0.70 mmol) andtriazolopyridinone 1-5 (150 mg, 0.70 mmol) were placed in a microwavevial and dissolved in NMP (1 mL). To the mixture was added catalyticpowdered KOH (7.9 mg, 0.14 mmol), and the vial was capped and heated at160° C. under microwave irradiation for 20 min. After cooling, themixture was diluted with CH₂Cl₂ (100 mL) and washed with water (25 mL)and brine (25 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The crude material was purified by silica gelflash column chromatography (40 g cartridge), eluting with 20-100%EtOAc/hexanes, then 1-10% EtOH/EtOAc. The fractions containing thedesired product (10-3) were pooled, and after solvent removal in vacuo,160 mg (62%) of a fluffy yellow solid were obtained. LC/MS: m/z(M+H)=370.0.

2-(2-(1,5-naphthyridin-2-yl)ethyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(10-4)

Triazolopyridinone 10-3 (22 mg, 0.059 mmol) and pyridin-4-ylboronic acid(11 mg, 0.089 mmol) were placed in a microwave vial and dissolved indioxane (1 mL). To the mixture was added 1 M aq. Cs₂CO₃ solution (0.12mL, 0.12 mmol). The mixture was then sparged with N₂ gas for 3 min, andbis(tri-tert-butylphosphine)palladium (3.0 mg, 0.006 mmol) was added.The vial was capped and heated at 100° C. under microwave irradiationfor 20 min. After cooling, the reaction mixture was diluted with EtOAc(30 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel flash column chromatography (12 g cartridge), eluting with 0-15%MeOH/CH₂Cl₂. The fractions containing the desired product (10-4) werepooled, and after solvent removal in vacuo, 5.0 mg (23%) of a semisolidwere obtained. ¹H NMR (300 MHz, CHCl₃-d): δ 8.95 (dd, J=4.2, 1.6 Hz,1H), 8.63 (dd, J=4.8, 1.5 Hz, 2H), 8.37-8.31 (m, 2H), 7.84 (dd, J=6.9,1.2 Hz, 1H), 7.71 (dd, J=4.8, 1.8 Hz, 2H), 7.63 (dd, J=8.7, 4.2 Hz, 1H),7.57 (d, J=9.0 Hz, 1H), 7.39 (dd, J=6.9, 1.2 Hz, 1H), 6.64 (t, J=6.9 Hz,1H), 4.65 (t, J=6.9 Hz, 2H), 3.60 (t, J=6.9 Hz, 2H). HRMS (ES) 369.1443found (M+H), 369.1461 required.

Example 11

1-methyl-4-phenyl-1H-imidazole (11-2)

In a 20 mL microwave vial were placed 11-1 (1.0 g, 6.94 mmol), cesiumcarbonate (4.52 g, 13.9 mmol) and DMF (35 mL). Iodomethane (1.09 g,0.477 mL, 7.63 mmol) was added, the vessel was sealed, and the solutionwas heated at 50° C. for 3 h. The reaction mixture was then diluted withEtOAc (100 mL) and sat. aq. NaHCO₃ (100 mL). The organic layer waswashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel flash columnchromatography (40 g cartridge), eluting with 0-70% EtOAc/hexanes over20 min to give 500 mg (46%) of 11-2. LC/MS: m/z (M+H)=159.1.

2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanol (11-3)

In a 25 ml flask were placed 11-2 (0.500 g, 3.16 mmol), and anhydrousTHF (6 mL). The reaction was flushed with N₂ gas and cooled to −78° C.Ethylene oxide (27.3 g, 31 mL, 31.6 mmol) was added dropwise viasyringe. Upon completion of addition, the reaction mixture was warmed toroom temperature and stirred for 18 hours. The reaction mixture was thenquenched with sat. aq. NH₄Cl (100 mL) and extracted with EtOAc (2×150mL). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel flash column chromatography (24 g cartridge),eluting with 0-100% EtOAc/hexanes to give 200 mg (31%) of 11-3. LC/MS:m/z (M+H)=203.2.

5-bromo-2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(11-4)

In 25 mL flask were placed 11-3 (0.200 g, 0.99 mmol), triphenylphosphine(0.26 g, 0.99 mmol), DIAD (0.200 g, 0.99 mmol) and THF (10 mL). Thereaction mixture was stirred for 10 min at room temperature. 12-3 (0.254g, 1.19 mmol) was then added and the reaction was stirred for 30 min.The mixture was concentrated in vacuo and purified by silica gel flashcolumn chromatography (24 g cartridge), eluting with 0-100%EtOAc/hexanes to give 100 mg (25%) of 11-4. LC/MS: m/z (M+H)=398.3. ¹HNMR (500 MHz, CHCl₃-d): δ 7.70 (d, J=7.7 Hz, 2H), 7.34 (t, J=7.6 Hz,2H), 7.21 (d, J=7.5 Hz, 1H), 7.10 (s, 1H), 7.02 (d, J=9.4 Hz, 1H), 6.82(dd, J=9.4, 6.8 Hz, 1H), 6.57 (d, J=6.8 Hz, 1H), 4.41 (t, J=7.7 Hz, 2H),3.67 (s, 3H), 3.25 (t, J=7.7 Hz, 2H). HRMS (ES) 398.0604 found (M+H),398.0614 required.

Example 12

2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-5-morpholino[1,2,4]thazolo[4,3-a]pyridin-3(2H)-one(12-1)

In a 2 mL microwave vial were placed 11-4 (0.025 g, 0.063 mmol) andmorpholine (0.459 g, 0.461 mL, 5.27 mmol). The vial was sealed andheated in an oil bath for 15 min at 120° C. The mixture was concentratedin vacuo and purified by reverse phase HPLC (5-50% MeCN/water with 0.01%TFA additive). Fractions containing pure product were treated with sat.aq. NaHCO₃ and extracted with EtOAc. The combined extracts were washedwith brine, dried over Na₂SO₄, and filtered. The filtrate was driedunder reduced pressure to give 8 mg (32%) of 12-1. LC/MS: m/z(M+H)=405.5. ¹H NMR (500 MHz, CHCl₃-d): δ 7.68 (d, J=7.7 Hz, 2H), 7.31(d, J=7.6 Hz, 2H), 7.21-7.16 (m, 1H), 7.08 (s, 1H), 6.91 (dd, J=9.3, 7.0Hz, 1H), 6.68 (d, J=9.3 Hz, 1H), 5.60 (d, J=7.3 Hz, 1H), 4.37 (t, J=7.5Hz, 2H), 3.90-3.86 (m, 4H), 3.74-3.70 (m, 2H), 3.64 (s, 3H), 3.21 (t,J=7.5 Hz, 2H), 2.96-2.87 (m, 2H). HRMS (ES) 405.2048 found (M+H),405.2035 required.

Example 13

trans-ethyl 2-(pyridin-2-yl)cyclopropanecarboxylate (13-3)

A solution of 2-vinylpyridine (13-1) (2 g, 19.0 mmol) in toluene (40 ml)was treated with ethyl diazoacetate (1.97 ml, 19.0 mmol) and stirred atreflux overnight. The mixture was concentrated in vacuo, and the residuewas purified by gradient elution on silica gel (0-50% EtOAc/hexanes) toelute peak 1; the solvent gradient was then ramped to 100% EtOAc toelute peak 2. This yielded the 13-3 (1.6 g, 44%) as the first elutingdiastereomer, and the corresponding cis diastereomer 13-2 (914 mg, 25%)as the second eluting diastereomer, both as yellow oils. ¹H NMR (500MHz, CDCl₃): δ 8.44 (m, 1H), 7.56 (dt, J=7.6, 1.7 Hz, 1H), 7.22 (dd,J=7.8, 1.0 Hz, 1H), 7.08 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 4.17 (q, J=7.3Hz, 2H), 2.58 (ddd, J=10.0, 6.1, 3.9 Hz, 1H), 2.25 (ddd, J=9.5, 5.6, 3.9Hz, 1H), 1.61, (m, 2H), 1.28 (t, J=7.1 Hz, 3H). LC/MS: m/z (M+H)=192.1.

(trans-2-(pyridin-2-yl)cyclopropyl)methanol (13-4)

A solution of 13-3 (751 mg, 3.93 mmol) in THF (20 mL) was cooled to 0°C. and treated slowly with lithium aluminum hydride (3.93 mL, 3.93 mmol,1 M solution in THF). The solution was warmed to room temperature andstirred for 20 min. The reaction mixture was then recooled to 0° C. andtreated sequentially dropwise with 0.15 mL of water, 0.15 ml of 15%NaOH, and 0.45 mL of water. Sodium sulfate was added to the mixture.After stirring at room temperature for 10 min, the mixture was filteredthrough a pad of Celite, and the filtrate was concentrated in vacuo toafford the title compound as a pale yellow oil. The material wassufficiently pure to use in the subsequent step without furtherpurification. LC/MS: m/z (M+H)=150.1.

5-bromo-2-(((1R,2R)-2-(pyridin-2-yl)cyclopropyl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(13-5)

In 100 mL round bottom flask were placed 13-4 (697 mg, 4.67 mmol), DIAD(945 mg, 4.67 mmol), and triphenylphosphine (1.23 g, 4.67 mmol) inanhydrous THF (46.7 mL).

After stirring the yellow reaction mixture for 10 min, 2-3 (1.00 g, 4.67mmol) was added in one portion. After 10 min, solvent was removed invacuo, and the crude product was purified by silica gel flash columnchromatography (120 g cartridge), eluting with 0-100% 1:1 EtOAc/(20:1:1EtOH/NH₄OH/H₂O)/hexanes to give 1.21 g (75%) of 13-5. LC/MS: m/z(M+H)=345.0.

5-morpholino-2-(((1R,2R)-2-(pyridin-2-yl)cyclopropyl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(13-6)

In a 1 mL microwave vial were placed 13-5 (22 mg, 0.064 mmol) andmorpholine (1.00 g, 1.00 mL, 11.5 mmol). The vial was sealed and heatedat 120° C. under microwave irradiation for 10 min. The reaction mixturewas directly purified by reversed phase chromatography to give 14.0 mg(62%) of 13-6. ¹H NMR δ (500 MHz, DMSO-d₆): δ 8.44 (d, J=5.0 Hz, 1H),7.81 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.01 (dd, J=9.3, 7.0Hz, 1H), 6.72 (d, J=9.3 Hz, 1H), 5.75 (d, J=7.0 Hz, 1H), 3.90 (dd,J=6.9, 3.9 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 3.12-3.03 (m, 4H), 2.25 (dt,J=8.5, 4.6 Hz, 1H), 1.84 (s, 1H), 1.23-1.15 (m, 2H). HRMS (ES) 352.1761(M+H) found, 352.1768 required.

The following compounds were prepared using the foregoing methodology,but substituting the appropriately substituted reagent, as described inthe foregoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature, orreadily synthesized by one skilled in the art of organic synthesiswithout undue experimentation. Final products were purified by eithergradient elution on SiO₂ (EtOAc/hexanes, MeOH/CH₂Cl₂, or 1:1EtOAc/(20:1:1 EtOH/NH₄OH/H₂O)/hexanes, reverse phase flashchromatography (MeCN/H₂O), or preparative thin layer chromatography(EtOAc/hexanes, MeOH/CH₂Cl₂, MeOH/EtOAc or 1:1 EtOAc/(20:1:1EtOH/NH₄OH/H₂O)/hexanes, and were isolated as free bases.

TABLE 1 Cpd. Structure Name HRMS m/z (M + H)  1-6

8-bromo-2-(2-quinolin-2- ylethyl[1,2,4]triazolo[4,3- a]pyridin-3(2H)-one369.0345 found, 369.0349 required.  2-4

5-bromo-2-(2-quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 369.0346 found, 369.0349 required.  3-4

6-bromo-2-(2-quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 369.0348 found, 369.0349 required.  4-1

8-(1,3-oxazol-2-yl)-2-(2- quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 358.1299 found, 358.1302 required.  5-1

5-pyridin-4-yl-2-(2-quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 368.1508 found, 368.1509 required.  6-1

5-morpholin-4-yl-2-(2-quinolin- 2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 376.1765 found, 376.1771 required.  7-2

5-[1-hydroxy-1-(4- methoxyphenyl)ethyl]-2-(2 - quinolin-2-ylethyl)[1,2,4]triazolo[4,3- a]pyridin-3(2H)-one 441.1911 found,441.1923 required.  8-2

3-oxo-N-pyridin-3-yl-2-(2- quinolin-2-ylethyl)-2,3-dihydro[1,2,4]triazolo[4,3- a]pyridine-5-carboxamide 411.1546 found,411.1567 required.  9-1

6-pyridin-3-yl-2-(2-quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 368.1502 found, 368.1509 required. 10-4

2-[2-(1,5-naphthyridin-2- yl)ethyl]-8-pyridin-4-yl[1,2,4]triazolo[4,3-a]pyridin- 3(2H)-one 369.1443 found, 369.1461required. A-1

5-pyridin-3-yl-2-(2-quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 368.1503 found, 368.1509 required. A-2

8-methyl-2-(2-quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 305.1400 found, 305.1400 required. A-3

5-(4-methylphenyl)-2-(2- quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 381.1715 found, 381.1713 required. A-4

2-(2-quinolin-2-ylethyl)-5-(1,3- thiazol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 374.1068 found, 374.1073 required. A-5

5-phenyl-2-(2-quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 367.1552 found, 367.1556 required. A-6

5-piperidin-1-yl-2-(2-quinolin-2- ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 374.1976 found, 374.1978 required. A-7

5-[(pyridin-3-ylmethyl)amino]- 2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3- a]pyridin-3(2H)-one 397.1773 found,397.1774 required. A-8

5-(1-hydroxy-1-methylethyl)-2- (2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3- a]pyridin-3(2H)-one 349.1659 found,349.1662 required. 11-4

5-bromo-2-[2-(1-methyl-4- phenyl-1H-imidazol-2-yl)ethyl][1,2,4]triazolo[4,3- a]pyridin-3(2H)-one 398.0604 found,398.0614 required. 12-1

2-[2-(1-methyl-4-phenyl-1H- imidazol-2-yl)ethyl]-5- morpholin-4-yl[1,2,4]triazolo[4,3-a]pyridin- 3(2H)-one 405.2048 found, 405.2035required. B-1

2-[2-(1-methyl-4-phenyl-1H- imidazol-2-yl)ethyl]-5-pyridin-4-yl[1,2,4]triazolo[4,3-a]pyridin- 3(2H)-one 397.1765 found, 397.1774required. 13-6

5-morpholino-2-(((1R,2R)-2- (pyridin-2- yl)cyclopropyl)methyl)-[1,2,4]triazolo[4,3-a]pyridin- 3(2H)-one 352.1761 found, 352.1768required.

The compounds of the following examples had activity in inhibiting thehuman PDE10 enzyme in the aforementioned assays with a K_(i) of about0.1 nM to about 100 nM: 1-6, 2-4, 4-1, 5-1, 6-1, 7-2, 8-2, A-1, A-2,A-3, A-4, A-5, A-6, A-7, A-8, 11-4, 12-1, B-1.

The compounds of the following examples had activity in inhibiting thehuman PDE10 enzyme in the aforementioned assays with a K_(i) of about0.1 nM to about 10 nM: 5-1, 6-1, A-1, 11-4, 12-1, B-1.

The following table shows representative data for the compounds of theExamples as PDE10 inhibitors as determined by the foregoing assayswherein the PDE10 K_(i) is a measure of the ability of the test compoundto inhibit the action of the PDE10 enzyme. Representative compounds ofthe invention had the K_(i) values specified below in theabove-described assay.

TABLE 2 Compound PDE10A K_(i) (nM) 1-6 37 2-4 59 3-4 155 4-1 22 5-1 4.46-1 2.5 7-2 11 8-2 97 9-1 510 10-4  103 A-1  9.0 A-2  74 A-3  17 A-4  23A-5  20 A-6  19 A-7  12 A-8  72 11-4  7.2 12-1  0.41 B-1  2.0 13-6  546

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula I:

wherein: A is heterocyclyl selected from the group consisting of (1)imidazolyl, and (2) quinolinyl; R^(1a), R^(1b) and R^(1c) may be absentif the valency of A does not permit such substitution and areindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(n)—C₁₋₆ alkyl, where m is 0 or1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) andwhere the alkyl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl,where the cycloalkyl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (6) —(C═O)_(m)—C₂₋₄ alkenyl, where thealkenyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (7) —(C═O)_(m)—C₂₋₄ alkynyl, where the alkynyl isunsubstituted or substituted with one or more substituents selected fromR¹³, (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where thephenyl or naphthyl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (9) —(C═O)_(m)—O_(n)-heteroaryl, wherethe heteraryl is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ andR¹¹ are independently selected from the group consisting of: (a)hydrogen, (b) C₁₋₆ alkyl, which is unsubstituted or substituted withR¹⁴, (c) C₃₋₆ alkenyl, which is unsubstituted or substituted with R¹⁴,(d) C₃₋₆ alkynyl, which is unsubstituted or substituted with R¹⁴, (e)C₃₋₆ cycloalkyl which is unsubstituted or substituted with R¹⁴, (f)phenyl, which is unsubstituted or substituted with R¹⁴, and (g)heteroaryl, which is unsubstituted or substituted with R¹⁴, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹²is selected from the definitions of R¹⁰ and R¹¹, (13) —CO₂H, (14) —CN,and (15) —NO₂; R^(2b) is hydrogen R^(2a), and R^(2c), are independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)hydroxyl, (4) —(C═O)_(m)—O_(n)—C₁₋₆ alkyl, where the alkyl isunsubstituted or substituted with one or more substituents of R¹³, (5)—(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R¹³, (6)—(C═O)_(m)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (7)—(C═O)_(m)—C₂₋₄ alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (9)—(C═O)_(m)—O_(n)-heterocyclyl, where the heterocyclyl is unsubstitutedor substituted with one or more substituents selected from R¹³, (10)—(C═O)_(m)—NR¹⁰R¹¹, (11) —S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H,(14) —CN, and (15) —NO₂; R³, R⁴, R⁵ and R⁶ are independently selectedfrom the group consisting of: (1) hydrogen, (2) halogen, and (3) —C₁₋₆alkyl, or R³ and R⁵ are joined together to form a cyclopropyl ring; R¹³is selected from the group consisting of: (1) halogen, (2) hydroxyl, (3)—(C═O)_(m)—O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹⁴, (4)—O_(n)—(C₁₋₃)perfluoroalkyl, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, wherethe cycloalkyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (6) —(C═O)_(m)—C₂₋₄ alkenyl, where thealkenyl is unsubstituted or substituted with one or more substituentsselected from R¹⁴, (7) —(C═O)_(m)—C₂₋₄ alkynyl, where the alkynyl isunsubstituted or substituted with one or more substituents selected fromR¹⁴, (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where thephenyl or naphthyl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (9) —(C═O)_(m)—O_(n)-heteroaryl, wherethe heteroaryl is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;R¹⁴ is selected from the group consisting of: (1) hydroxyl, (2) halogen,(3) C₁₋₆ alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6) —O(C═O)—C₁₋₆alkyl, (7) —NH—C₁₋₆alkyl, (8) phenyl, (9) heteroaryl, (10) —CO₂H, and(11) —CN; p is 0 or 1, wherein when p is 0 a bond is present; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1 ofthe formula Ia:

Ia or a pharmaceutically acceptable salt thereof.
 3. The compound ofclaim 1 wherein A is quinolinyl.
 4. The compound of claim 1 wherein A isimidazolyl.
 5. The compound of claim 1 wherein R^(2b) is hydrogen, andR^(2a) and R^(2c) are independently selected from the group consistingof: (1) hydrogen, (2) chloro, (3) fluoro, (4) bromo, (5) methyl, (6)isopropoxy, (7) methoxy, (8) t-butoxy, (9) imidazolyl, (10)isothiazolyl, (11) oxazolyl, (12) morpholinyl, (13) pyrazolyl, (14)pyridyl, (15) tetrazolyl, and (16) thiazolyl.
 6. The compound of claim 1wherein R³ is hydrogen, R⁴ is hydrogen, R⁵ is hydrogen, and R⁶ ishydrogen.
 7. A compound which is selected from the group consisting of:8-bromo-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-bromo-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;6-bromo-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;8-(oxazol-2-yl)-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-(pyridin-4-yl)-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-morpholino-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-(2-hydroxy-1-(4-methoxyphenyl)propan-2-yl)-2-(2-(quinolin-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;3-oxo-N-(pyridin-3-yl)-2-(2-(quinolin-2-yl)ethyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxamide;5-bromo-2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-5-morpholino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;58-bromo-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-bromo-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;6-bromo-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;8-(1,3-oxazol-2-yl)-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-pyridin-4-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-morpholin-4-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-[1-hydroxy-1-(4-methoxyphenyl)ethyl]-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;3-oxo-N-pyridin-3-yl-2-(2-quinolin-2-ylethyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxamide;6-pyridin-3-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-pyridin-3-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;8-methyl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-(4-methylphenyl)-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;2-(2-quinolin-2-ylethyl)-5-(1,3-thiazol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-phenyl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-piperidin-1-yl-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-[(pyridin-3-ylmethyl)amino]-2-(2-qyinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-(1-hydroxy-1-methylethyl)-2-(2-quinolin-2-ylethyl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;5-bromo-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl]-5-morpholin-4-yl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl]-5-pyridin-4-yl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;and or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier and acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 9. Acompound of claim 1 or a pharmaceutically acceptable salt thereof foruse in medicine.